Paget's Disease Of Bone Research Articles

P.83Vacuolar myopathy with valosin containing protein (VCP)-positive intranuclear and cytoplasmic inclusions: report of two cases with early and late childhood-onset disease

Paediatric-onset protein aggregation and vacuolar myopathies (PAVM) are rare familial or sporadic disorders with marked clinicopathological and genetic heterogeneity. Extensive pathological analysis may be required to direct genetic testing. A multisystem proteinopathy (MSP) causing several phenotypes in adults including rimmed vacuolar myopathy, motor neurone disease, frontotemporal dementia and Paget disease of bone, unified by ubiquitin/TDP-43+ inclusions has been linked to mutations in VCP, HNRNPA2B1, HNRNPA1 and SQSTM1. Intranuclear/cytoplasmic VCP+ inclusions are present in most cases of VCP-MSP. VCP+ aggregates are hitherto not reported in other PAVM except sporadic inclusion body myositis and few neurodegenerative disorders. We describe two clinically diverse early and late-childhood onset cases with unifying muscle pathology resembling the classic VCP-MSP. PI, a 21-year-old male presented at 16y with aching pain in his left forearm and progressive left hand finger contractures. Remaining assessment was normal. PII, a 22-year old female presented at 9y with toe-walking and delayed motor milestones. Weakness progressed rapidly and ambulation was lost at 14y. She is now fully wheelchair-dependent, and on long-term non-invasive ventilation. PI: normal CK and EMG myopathic in the left forearm and intrinsic hand muscles. Muscle MRI showed oedema and fatty infiltration in the left forearm and finger flexors. PII: CK 409, EMG myopathic. Muscle biopsies (PI, PII): identical pathology resembling classic VCP-inclusion body myopathy with chronic myopathic/dystrophic changes, rimmed vacuoles, sarcoplasmic and intranuclear protein aggregates/inclusions (VCP/ubiquitin/TDP43+) and tubulofilamentous inclusions. Genetic studies to date are negative including whole exome sequencing in PII. Further genetic diversity may underpin the unifying VCP+ inclusion body pathology in these cases. Recruitment to other next-generation-sequencing platforms is underway.

OSTEOSARCOMA IN PAGET DISEASE OF BONE

Background Paget disease of bone (PDB) is a disorder of bone metabolism that involves osteoclasts. Osteosarcoma arising in Paget disease is a rare complication of PDB occurring in less than 1% of all osteosarcomas. The aim of this case report is to describe different imaging features of osteosarcomas arising in PDB and its progression. Clinical and Radiographic Findings A 72-year-old female with known arthritis and PDB presented to the emergency room with a 1-week headache and right temporal/parietal skull swelling. The erythrocyte sedimentation rate (ESR) and serum alkaline phosphatase (ALK) were elevated. Planar radiographs of the skull exhibited mixed sclerotic and radiolucent lesions throughout, giving a cottonwool appearance. Multidetector computed tomography (MDCT) of the head showed peripheral enhancement, a partially calcified right temporal region mass, and expansion of the underlying calvarium with a periosteal reaction. Intracranial extension was clear on magnetic resonance imaging (MRI). Furthermore, positron emission tomography/computed tomography (PET/CT) revealed increased fluorodeoxyglucose (FDG) avidity in the solitary right temporal/parietal lesion. Biopsy revealed osteosarcoma with chondroblastic features arising in PDB. The patient underwent right craniectomy and resection of the tumor. Six weeks later, gross recurrent disease at the resection site was found on a head MDCT that demonstrated soft tissue density underlying the cranioplasty with a significant amount of vasogenic edema involving the temporal/frontal lobe. The patient underwent right decompressive and epidural tumor resection. A day later, she was pronounced brain dead. Discussion/Conclusions PDB is often diagnosed through incidental findings in a regular blood chemistry panel, particularly ALK, or through imaging done for another reason. The planar radiograph gives the best clue to the presence of PDB. The MDCT is mandatory for better outcomes in treatment of osteosarcoma, whereas MRI is best for depicting local intracranial extension. PET identifies the region of a tumor through FDG increase. Lastly, biopsy is necessary for confirming the tumor. Paget disease of bone (PDB) is a disorder of bone metabolism that involves osteoclasts. Osteosarcoma arising in Paget disease is a rare complication of PDB occurring in less than 1% of all osteosarcomas. The aim of this case report is to describe different imaging features of osteosarcomas arising in PDB and its progression. A 72-year-old female with known arthritis and PDB presented to the emergency room with a 1-week headache and right temporal/parietal skull swelling. The erythrocyte sedimentation rate (ESR) and serum alkaline phosphatase (ALK) were elevated. Planar radiographs of the skull exhibited mixed sclerotic and radiolucent lesions throughout, giving a cottonwool appearance. Multidetector computed tomography (MDCT) of the head showed peripheral enhancement, a partially calcified right temporal region mass, and expansion of the underlying calvarium with a periosteal reaction. Intracranial extension was clear on magnetic resonance imaging (MRI). Furthermore, positron emission tomography/computed tomography (PET/CT) revealed increased fluorodeoxyglucose (FDG) avidity in the solitary right temporal/parietal lesion. Biopsy revealed osteosarcoma with chondroblastic features arising in PDB. The patient underwent right craniectomy and resection of the tumor. Six weeks later, gross recurrent disease at the resection site was found on a head MDCT that demonstrated soft tissue density underlying the cranioplasty with a significant amount of vasogenic edema involving the temporal/frontal lobe. The patient underwent right decompressive and epidural tumor resection. A day later, she was pronounced brain dead. PDB is often diagnosed through incidental findings in a regular blood chemistry panel, particularly ALK, or through imaging done for another reason. The planar radiograph gives the best clue to the presence of PDB. The MDCT is mandatory for better outcomes in treatment of osteosarcoma, whereas MRI is best for depicting local intracranial extension. PET identifies the region of a tumor through FDG increase. Lastly, biopsy is necessary for confirming the tumor.

OSTEOPATHIA STRIATA WITH CRANIAL SCLEROSIS

Background Osteopathia striata with cranial sclerosis (OSCS) is a rare x-linked genetic disorder that has variable clinical findings but specific radiographic features, which include marked sclerosis of the long bones and axial skeleton, including the skull. Linear striations, commonly seen in the long bones, are the basis for the name osteopathia striata. Maxillofacial manifestations can include a cleft palate, high palatal vault, midface hyperplasia, hypoplastic maxillary sinuses, enlarged alveolar bone processes, temporomandibular joint (TMJ) abnormalities, and dense mandibular bone with variable striations. Dental abnormalities have been poorly documented but include delayed eruption of permanent teeth, missing teeth, short roots, and microdontia. Study Design A 44-year-old male was referred to the University of Florida College of Dentistry for evaluation and treatment of temporomandibular disorder (TMD). A pantomograph was exposed to assess TMJ dysfunction related to progressive bony overgrowth of craniomaxillofacial skeleton and ankylosis, which had previously been surgically treated. His medical history was significant for OSCS, cleft lip and palate, obstructive sleep apnea, bronchitis, asthma, disk herniation, arthritis, diabetes, and chronic kidney disease. The radiographic assessment was limited because of severe sclerosis of the cranium, displayed as multiple lobulated appearances and homogeneous radiopaque entities superimposed on the maxilla, TMJs, and the sphenoid, mastoid, and temporal bones. The visualized cortical outlines of the maxilla and the mandible appeared dense, thick, and sclerotic. Discussion/Conclusions OSCS is a rare disorder. Diagnosis can often be challenging because other diseases, such as osteopetrosis, pyknodysostosis, Paget disease of bone, and other sclerosing bone dysplasias, make this difficult to diagnose. Radiologists should be aware of the specific radiographic appearance of this condition to aid in the proper diagnosis and management of these patients.

C9ORF72 hexanucleotide repeat expansion frequency in patients with Paget's disease of bone

Paget's disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. A strong genetic component has been shown in PDB, and variants in several genes, such as SQSTM1, VCP, and OPTN, have been associated with the disease. Mutations in the same genes have also been reported in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Hexanucleotide repeat expansions in the C9ORF72 gene have been shown to be responsible for both familial and sporadic frontotemporal dementia/amyotrophic lateral sclerosis. Thence, we evaluated the frequency of the C9ORF72 hexanucleotide repeat expansions in a cohort of 191 Italian PDB patients and in 106 controls. The pathogenic repeat expansion was detected in 2 PDB patients (1.0%). During the follow-up period, both PDB patients did not develop any sign of mental decline and/or motor neuron disease. Our study suggests that repeat expansions in the C9ORF72 gene are rare in patients with PDB.

Paget Disease of Bone: Current Concepts

Paget Disease of Bone: Current Concepts

Vitamin D Status in Paget Disease of Bone and Efficacy-Safety Profile of Cholecalciferol Treatment in Pagetic Patients with Hypovitaminosis D.

Adequate vitamin D status is essential for skeletal health. Paget's disease of bone (PDB) is a common metabolic skeletal disorder, but data regarding the vitamin D status in PDB patients are lacking. We performed a case-control study to estimate vitamin D status in 708 PDB patients and in 1803 healthy controls from Italy and an observational prospective study to evaluate the efficacy-safety profile of oral cholecalciferol treatment [400.000 International Units (UI) of cholecalciferol administered in cycles of 8weeks until 25OHD levels reaches 70nmol/L as primary therapy and 50.000UI of cholecalciferol administered every 2weeks for 52weeks for the maintenance therapy] in 82 PDB patients with hypovitaminosis D, i.e., 25OHD < 50nmol/L. The main outcome measures for the prospective study were 25OHD levels, metabolic risk factors (RF) for nephrolithiasis, bone pain score (BPS), and pain medication score (PMS). Over half of PDB patients had hypovitaminosis D. Among PDB patients treated with cholecalciferol, 76 patients reached 25OHD levels ≥ 70nmol/L after the first cycle of primary therapy and the remaining six patients after a second cycle. The maintenance therapy guaranteed 25OHD levels ≥ 70nmol/L during the entire follow-up. The increase in 25OHD levels reduced PTH, BPS, and PMS levels, without changes in RF for nephrolithiasis. We can conclude that (i) hypovitaminosis D is frequent in PDB patients, (ii) cholecalciferol significantly increased 25OHD levels in PDB patients, and (iii) the correction of hypovitaminosis D improves the quality of life of PDB patients without inducing significant changes in RF for nephrolithiasis.

Long-term control of Paget’s disease of bone with low-dose, once-weekly, oral bisphosphonate preparations, in a “real world” setting

Bisphosphonates are the mainstay of the treatment of Paget’s disease of bone (PDB). Clinical practice guidelines recommend treatment with intravenous zoledronic acid or high-dose oral nitrogen bisphosphonates (N-BPs). We present our long-term experience treating PDB patients with lower than recommended oral doses of N-BPs, equivalent to once-weekly doses used for treating osteoporosis. PDB patients were seen, between 1990 and 2015 at the endocrine clinic of an academic medical center. Diagnosis was established according to accepted criteria. Patients were initially treated with alendronate 70 mg/week or risedronate 35 mg/week. Whenever the initial dose failed to produce remission, the dosage was increased to twice a week the respective dose. Patients were followed for a mean of 11.9 years (range: 1.7–24.8). Out of 96 treatment courses with N-BPs, 89% were with alendronate and 11% with risedronate. Remission was achieved in 84% of the courses with alendronate 70 mg/week. 90% of those who did not achieve remission subsequently responded to 140 mg/week. Out of the 8 treatment courses with risedronate 35 mg/week, 87% achieved remission, and the 2 patients who did not achieve remission subsequently responded to 70 mg/week. The median duration of remissions following 3-4 months courses of alendronate 70 mg/week or risedronate 35 mg/week was 8.8 months (IQR: 5.5, 14.8). In a large proportion of “real world” PDB patients, remission can be achieved with once-weekly, “osteoporosis doses” of alendronate or risedronate.

Evaluation of Bone Metabolism Biomarkers in Paget's Disease of Bone.

Objective: To evaluate serum levels of bone metabolism biomarkers in patients with Paget's disease of bone (PDB).Methods: Serum levels of osteopontin, sclerostin, receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin, Dickkopf-related protein 1 (DKK-1), and soluble frizzled-related protein 1 (sFRP-1) were measured in 57 patients with Paget’s disease of bone and 24 controls with primary osteoarthritis. Subgroup analysis was employed to identify any differences in bone metabolism biomarker levels according to disease activity or current treatment.Results: Patients with PDB presented higher levels of osteopontin and RANKL. When compared with patients with inactive disease, patients with active disease presented higher levels of bone-specific alkaline phosphatase (BAP) and osteopontin. There was a significant correlation between serum levels of BAP and osteopontin. There was no significant correlation between levels of BAP and other bone metabolism biomarkers. Current disease extension on bone scintigraphy had a significant correlation with serum levels of osteopontin and BAP. There was no significant correlation between current disease extension and other bone metabolism biomarkers. Serum levels of osteopontin and RANKL were correlated to serum levels of BAP and disease extension.Conclusion: Patients with PDB presented higher levels of osteopontin and RANKL. Osteopontin could be a useful biomarker for activity and extension of PDB.

Disruption of valosin-containing protein activity causes cardiomyopathy and reveals pleiotropic functions in cardiac homeostasis

Valosin-containing protein (VCP), also known as p97, is an ATPase with diverse cellular functions, although the most highly characterized is targeting of misfolded or aggregated proteins to degradation pathways, including the endoplasmic reticulum-associated degradation (ERAD) pathway. However, how VCP functions in the heart has not been carefully examined despite the fact that human mutations in VCP cause Paget disease of bone and frontotemporal dementia, an autosomal dominant multisystem proteinopathy that includes disease in the heart, skeletal muscle, brain, and bone. Here we generated heart-specific transgenic mice overexpressing WT VCP or a VCPK524A mutant with deficient ATPase activity. Transgenic mice overexpressing WT VCP exhibit normal cardiac structure and function, whereas mutant VCP-overexpressing mice develop cardiomyopathy. Mechanistically, mutant VCP-overexpressing hearts up-regulate ERAD complex components and have elevated levels of ubiquitinated proteins prior to manifestation of cardiomyopathy, suggesting dysregulation of ERAD and inefficient clearance of proteins targeted for proteasomal degradation. The hearts of mutant VCP transgenic mice also exhibit profound defects in cardiomyocyte nuclear morphology with increased nuclear envelope proteins and nuclear lamins. Proteomics revealed overwhelming interactions of endogenous VCP with ribosomal, ribosome-associated, and RNA-binding proteins in the heart, and impairment of cardiac VCP activity resulted in aggregation of large ribosomal subunit proteins. These data identify multifactorial functions and diverse mechanisms whereby VCP regulates cardiomyocyte protein and RNA quality control that are critical for cardiac homeostasis, suggesting how human VCP mutations negatively affect the heart.

Tartrate-resistant acid phosphatase 5b, but not periostin, is useful for assessing Paget's disease of bone.

Periostin is a matricellular protein with a preferential location in cortical bone and periosteal tissue, and tartrate-resistant acid phosphatase 5b (TRAP5b) is a marker of osteoclast numbers. In Paget's disease of bone (PDB), there is increased cortical thickening and probably increased periosteal apposition, along with increased osteoclast numbers. To analyse if circulating periostin is a biomarker for PDB, and if it is associated with disease activity and involvement of long bones that represent major cortical contribution. Also, to analyse whether TRAP5b, a scarcely explored bone resorption marker, is useful in the assessment of PDB. We recruited 42 patients with PDB (13F/29M; 71 ± 11.6 yrs). 71.4% had active disease, 66.6% had polyostotic disease and 54.8% had long bone involvement. Blood and urine samples were taken between 8:00 and 10:00 A.M. after an overnight fast. Periostin and TRAP5b were measured in serum, using commercial ELISA assays (Biomedica and IDS, respectively). Serum total ALP, PINP, CTX, bone ALP and urinary NTX were measured. Reference values for periostin and TRAP5b were obtained from 45 healthy subjects. Serum periostin did not differ between patients and controls (989.4 ± 173.2 vs. 966.9 ± 195.4 pMol/L, p = 0.572). No significant differences were observed between patients with and without active disease (964.5 ± 168.8 vs.1051.6 ± 175.6 pMol/L, p = 0.143), involvement or not of long bones (1022.2 ± 145.8 vs 949.7 ± 198.2 pMol/L, p = 0.181) and monostotic or polyostotic disease (963.8 ± 198.7 vs 1002.2 ± 161.4 pMol/L, p = 0.505). There were significant correlations between serum periostin and all bone turnover markers (bone ALP, PINP, uNTX, sCTX and TRAP5b) in PDB patients with active disease, but not in the inactive PDB group. Serum TRAP5b was significantly higher in PDB patients than in controls (4.43 ± 1.76 vs. 3.21 ± 1.02 U/L, p < 0.001), in those with active disease (4.98 ± 1.76 vs. 3.07 ± 0.72 U/L, p < 0.001) and in patients with polyostotic disease than in those with monostotic disease (4.81 ± 1.79 vs 3.68 ± 1.5 U/L, p = 0.005). TRAP5b levels were not influenced by previous bisphosphonate treatment (4.14 ± 1.42 vs. 4.84 ± 2.02 U/L, p = 0.206). Periostin is not useful for assessing PDB, whilst TRAP5b, which has been a scarcely explored bone turnover marker until now, may be useful in the analysis of this disease, providing new information on the resorption process. In addition, periostin levels correlate with all classical BTMs in active PDB, suggesting that this marker may reflect periosteal and cortical metabolism in accelerated bone turnover states.

Molecular insights into an ancient form of Paget’s disease of bone

Paget's disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals older than 55 y of age. PDB-like changes have been reported in archaeological remains as old as Roman, although accurate diagnosis and natural history of the disease is lacking. Six skeletons from a collection of 130 excavated at Norton Priory in the North West of England, which dates to medieval times, show atypical and extensive pathological changes resembling contemporary PDB affecting as many as 75% of individual skeletons. Disease prevalence in the remaining collection is high, at least 16% of adults, with age at death estimations as low as 35 y. Despite these atypical features, paleoproteomic analysis identified sequestosome 1 (SQSTM1) or p62, a protein central to the pathological milieu of PDB, as one of the few noncollagenous human sequences preserved in skeletal samples. Targeted proteomic analysis detected >60% of the ancient p62 primary sequence, with Western blotting indicating p62 abnormalities, including in dentition. Direct sequencing of ancient DNA excluded contemporary PDB-associated SQSTM1 mutations. Our observations indicate that the ancient p62 protein is likely modified within its C-terminal ubiquitin-associated domain. Ancient miRNAs were remarkably preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression consistent with that reported in contemporary PDB-associated bone tumors. Our work displays the use of proteomics to inform diagnosis of ancient diseases such as atypical PDB, which has unusual features presumably potentiated by yet-unidentified environmental or genetic factors.

Abstract #208 Paget Disease of Bone with Normal Alkaline Phosphatase

Abstract #208 Paget Disease of Bone with Normal Alkaline Phosphatase

Diagnosis and Management of Paget's Disease of Bone in Adults: A Clinical Guideline.

ABSTRACTAn evidence‐based clinical guideline for the diagnosis and management of Paget's disease of bone (PDB) was developed using GRADE methodology, by a Guideline Development Group (GDG) led by the Paget's Association (UK). A systematic review of diagnostic tests and pharmacological and nonpharmacological treatment options was conducted that sought to address several key questions of clinical relevance. Twelve recommendations and five conditional recommendations were made, but there was insufficient evidence to address eight of the questions posed. The following recommendations were identified as the most important: 1) Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of metabolically active disease in patients with PDB. 2) Serum total alkaline phosphatase (ALP) is recommended as a first‐line biochemical screening test in combination with liver function tests in screening for the presence of metabolically active PDB. 3) Bisphosphonates are recommended for the treatment of bone pain associated with PDB. Zoledronic acid is recommended as the bisphosphonate most likely to give a favorable pain response. 4) Treatment aimed at improving symptoms is recommended over a treat‐to‐target strategy aimed at normalizing total ALP in PDB. 5) Total hip or knee replacements are recommended for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate. There is insufficient information to recommend one type of surgical approach over another. The guideline was endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone Research Society (UK), and the British Geriatric Society. The GDG noted that there had been a lack of research on patient‐focused clinical outcomes in PDB and identified several areas where further research was needed. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Cotton Wool Sign in Paget Disease of Bone.

Cotton Wool Sign in Paget Disease of Bone.

Targeted sequencing of DCSTAMP in familial Paget's disease of bone

Paget's disease of bone (PDB) has a strong genetic component. Variants in SQSTM1 are found in up to 40% of patients with a family history of the disease, where a pattern of autosomal dominance with incomplete penetrance is apparent. By contrast, SQSTM1 variants are only found in up to 10% of patients with sporadic disease. It has been hypothesised that the remaining genetic susceptibility to PDB, particularly in familial cases, could be explained by rare genetic variants in loci previously identified by Genome Wide Association Studies. It is likely that polygenic factors are involved in many individuals. In this study we utilised whole exome sequencing to investigate predisposing genetic factors in an unsolved PDB kindred and identified a c.1189C > T p.L397F variant in DC-STAMP, also known as TM7SF4, that co-segregated with disease. DCSTAMP was identified as a gene of interest in PDB following Genome Wide Association Studies and has been previously shown to play critical roles in osteoclast fusion. The variant we identified has also been reported in association with PDB in a French-Canadian cohort however the significance of this variant was inconclusive. Targeted screening of DCSTAMP in our familial cohort of PDB patients revealed an additional 8 variants; however we did not find a significant association between any of these, including p.L397F, with PDB. Osteoclastogenesis assays from the affected proband and his unaffected brother demonstrated an increase in osteoclast number and nucleation, consistent with the pagetic phenotype. In converse to other established Paget's associated genetic variations such as SQSTM1, TNFRSF11A and OPTN, expression of the mutant DC-STAMP protein attenuated the activation of transcription factors NFκB and AP-1 when exogenously expressed. We found that the p.L397F variant did not influence the subcellular localization of the protein. Based on these findings we conclude that genetic variation in DCSTAMP is not a significant predisposing factor in our specific cohort of PDB patients and the p.L397F variant is unlikely to be a contributing factor in PDB pathogenesis.

Rare Inherited forms of Paget's Disease and Related Syndromes.

Several rare inherited disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB) and in which PDB is a component of a multisystem disorder affecting muscle and the central nervous system. These conditions are the subject of this review article. Insertion mutations within exon 1 of the TNFRSF11A gene, encoding the receptor activator of nuclear factor kappa B (RANK), cause severe PDB-like disorders including familial expansile osteolysis, early-onset familial PDB and expansile skeletal hyperphosphatasia. The mutations interfere with normal processing of RANK and cause osteoclast activation through activation of nuclear factor kappa B (NFκB) independent of RANK ligand stimulation. Recessive, loss-of-function mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB and here the bone disease is due to unopposed activation of RANK by RANKL. Multisystem proteinopathy is a disorder characterised by myopathy and neurodegeneration in which PDB is often an integral component. It may be caused by mutations in several genes including VCP, HNRNPA1, HNRNPA2B1, SQSTM1, MATR3, and TIA1, some of which are involved in classical PDB. The mechanisms of osteoclast activation in these conditions are less clear but may involve NFκB activation through sequestration of IκB. The evidence base for management of these disorders is somewhat limited due to the fact they are extremely rare. Bisphosphonates have been successfully used to gain control of elevated bone remodelling but as yet, no effective treatment exists for the treatment of the muscle and neurological manifestations of MSP syndromes.

Genetic Variation in RIN3 in the Belgian Population Supports Its Involvement in the Pathogenesis of Paget's Disease of Bone and Modifies the Age of Onset.

Paget's disease of bone (PDB) is a common, late-onset bone disorder characterized by focal increase of bone turnover. Mutations in the SQSTM1 gene are found in up to 40% of patients and recent GWAS have led to novel associations with several loci. RIN3, the candidate gene located at the associated 14q32 locus, has recently been studied in a British cohort to elucidate its contribution to the pathogenesis. In this study, we performed a genetic screening of RIN3 in an unrelated cohort to validate these findings and to further explore genetic variation in this gene in the context of PDB. In our screening, we examined the 5' untranslated region (UTR), the exonic regions and the intron-exon boundaries of the gene in a control cohort and a patient cohort. Our findings show clustering of variation similar to the British cohort and support a protective role for common genetic variation (rs117068593, p.R279C) in the proline-rich region and a functionally relevant role for rare genetic variation in the domains that mediate binding and activation of its interaction partner, Rab5. Additive regression models, fitted for the common variants, validated the association of the rs117068593 variant with the disease (OR+/+ 0.315; OR+/- 0.562). In addition, our analyses revealed a potentially modifying effect of this variant on the age of onset of the disease. In conclusion, our findings support the involvement of genetic variation in RIN3 in PDB and suggest a role for RIN3 as a potential modifier of the age of onset of the disease.

Genetic regulatory mechanisms in human osteoclasts suggest a role for the STMP1 and DCSTAMP genes in Paget\u2019s disease of bone

Paget’s disease of bone (PDB) is characterised by focal abnormalities of bone remodelling, with increased osteoclastic resorption the primary feature of the disease. Genetic factors have been shown to play an important role in PDB, and genome-wide association studies (GWAS) have identified 7 genetic loci as associated with PDB at the genome-wide level. Expression quantitative trait locus (eQTL) studies using cell types that are directly relevant to the disease of interest are increasingly being used to identify putative effector genes for GWAS loci. We have recently constructed a unique osteoclast-specific eQTL resource using cells differentiated in vitro from 158 subjects for study of the genetics of bone disease. Considering the major role osteoclasts have in PDB, we used this resource to investigate potential genetic regulatory effects for the 7 PDB genome-wide significant loci on genes located within 500 kb of each locus. After correction for multiple testing, we observed statistically significant associations for rs4294134 with expression of the gene STMP1, and rs2458413 with expression of the genes DPYS and DCSTAMP. The eQTL associations observed for rs4294134 with STMP1, and rs2458413 with DCSTAMP were further supported by eQTL data from other tissue types. The product of the STMP1 gene has not been extensively studied, however the DCSTAMP gene has an established role in osteoclast differentiation and the associations seen between rs2458413 and PDB are likely mediated through regulatory effects on this gene. This study highlights the value of eQTL data in determining which genes are relevant to GWAS loci.

Paget's Disease of Bone.

Paget's disease of bone (PDB) is a chronic and focal bone disorder, characterized by increased osteoclast-mediated bone resorption and a subsequent compensatory increase in bone formation, resulting in a disorganized mosaic of woven and lamellar bone at one or more affected skeletal sites. As a result, bone pain, noticeable deformities, arthritis at adjacent joints, and fractures can occur. In a small proportion of cases neoplastic degeneration in osteosarcoma, or, less frequently, giant cell tumor has been also described at PDB sites. While recent epidemiological evidences clearly indicate a decrease in the prevalence and the severity of PDB, over the past 2 decades there have been consistent advances on the genetic mechanisms of disease. It is now clear that PDB is a genetically heterogeneous disorder, with mutations in at least two different genes (SQSTM1, ZNF687) and more common predisposing variants. As a counterpart to the genetic hypothesis, the focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. The exact nature of these triggers and how they might interact with the genetic factors are less understood, but recent experimental data from mice models suggest the implication of paramixoviral infections. The clinical management of PDB has also evolved considerably, with the development of potent aminobisphosphonates such as zoledronic acid which, given as a single intravenous infusion, now allows a long-term disease remission in the majority of patients.

Osteosarcoma arising from preexisting Paget's disease of bone

Paget's disease of bone (PDB) was first described by Sir James Paget in 1877 and is a relatively benign metabolic bone disease. It is believed to be a more common among European populations but is rare among Scandinavian and Asian populations. Malignant transformation is a rare, but fatal complications of PDB can occur, and most patients are elderly. Herein, we present a case of a tumor detected incidentally at the left proximal femur that was initially treated as metastatic bone disease, but the final pathology was proven to be secondary malignant transformation from preexisting PDB. Recent studies suggest that PDB may be under-represented in Asian populations. Thus, it is important that physicians pay more attention to PDB and its treatments. Early interventions and novel therapeutic agents can achieve better disease control and also prevent the complication of malignant transformation, which still has a poor prognosis.